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Ectopic expression of Zmiz1 induces cutaneous squamous cell malignancies in a mouse model of cancer.

Rogers LM, Riordan JD, Swick BL, Meyerholz DK, Dupuy AJ - J. Invest. Dermatol. (2013)

Bottom Line: Here we show that transposon-induced mutations in Zmiz1 drive expression of a truncated transcript that is similar to an alternative endogenous ZMIZ1 transcript found to be overexpressed in human SCCs relative to normal skin.In addition, we found that the alternative Zmiz1 isoform has greater protein stability than its full-length counterpart.Finally, we provide evidence that ZMIZ1 is overexpressed in a significant percentage of human breast, ovarian, and colon cancers in addition to human SCCs, suggesting that ZMIZ1 may play a broader role in epithelial cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

ABSTRACT
Cutaneous squamous cell carcinoma (SCC) is the second most common form of cancer in the human population, yet the underlying genetic mechanisms contributing to the disease are not well understood. We recently identified Zmiz1 as a candidate oncogene in nonmelanoma skin cancer through a transposon mutagenesis screen. Here we show that transposon-induced mutations in Zmiz1 drive expression of a truncated transcript that is similar to an alternative endogenous ZMIZ1 transcript found to be overexpressed in human SCCs relative to normal skin. We also describe an original mouse model of invasive keratoacanthoma driven by skin-specific expression of the truncated Zmiz1 transcript. Unlike most mouse models, Zmiz1-induced skin tumors develop rapidly and in the absence of promoting agents such as phorbol esters. In addition, we found that the alternative Zmiz1 isoform has greater protein stability than its full-length counterpart. Finally, we provide evidence that ZMIZ1 is overexpressed in a significant percentage of human breast, ovarian, and colon cancers in addition to human SCCs, suggesting that ZMIZ1 may play a broader role in epithelial cancers.

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Related in: MedlinePlus

Tumor-specific expression of ZMIZ1short(a) Diagram of the ZMIZ1 locus in mouse and human. The human alternative promoter is located in intron 6 and drives expression of the ZMIZ1short transcript. This transcript is similar to the transcript produced by SB transposon insertion into mouse intron 8. (b) The amino acid sequence of human and mouse short-forms differs by approximately 60 amino acids at the N-termini, but are otherwise nearly identical. Note that both full-length and ZMIZ1short contain all currently annotated functional protein domains. (c) RT-PCR analysis confirmed that ZMIZ1short is expressed in MCF7, but not in the other human cell lines tested. (d) Quantitative RT-PCR performed on human SCCs shows increased tumor-specific expression of ZMIZ1short. Dotted lines indicate the average Ct values for normal skin.
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Figure 1: Tumor-specific expression of ZMIZ1short(a) Diagram of the ZMIZ1 locus in mouse and human. The human alternative promoter is located in intron 6 and drives expression of the ZMIZ1short transcript. This transcript is similar to the transcript produced by SB transposon insertion into mouse intron 8. (b) The amino acid sequence of human and mouse short-forms differs by approximately 60 amino acids at the N-termini, but are otherwise nearly identical. Note that both full-length and ZMIZ1short contain all currently annotated functional protein domains. (c) RT-PCR analysis confirmed that ZMIZ1short is expressed in MCF7, but not in the other human cell lines tested. (d) Quantitative RT-PCR performed on human SCCs shows increased tumor-specific expression of ZMIZ1short. Dotted lines indicate the average Ct values for normal skin.

Mentions: We recently identified Zmiz1 as a cancer gene important for the induction of cutaneous SCC using SB transposon mutagenesis (Dupuy et al., 2009). Significantly, all insertions were located within intron 8, and oriented in such a way as to promote expression of a truncated transcript including exons 9-24 (Figure 1a). Importantly, the SB-induced transcript strongly resembles an endogenous human ZMIZ1 isoform (uc001kag-2), which includes an alternative promoter and exon that is spliced into exon 7 of the full-length transcript (Figure 1a).


Ectopic expression of Zmiz1 induces cutaneous squamous cell malignancies in a mouse model of cancer.

Rogers LM, Riordan JD, Swick BL, Meyerholz DK, Dupuy AJ - J. Invest. Dermatol. (2013)

Tumor-specific expression of ZMIZ1short(a) Diagram of the ZMIZ1 locus in mouse and human. The human alternative promoter is located in intron 6 and drives expression of the ZMIZ1short transcript. This transcript is similar to the transcript produced by SB transposon insertion into mouse intron 8. (b) The amino acid sequence of human and mouse short-forms differs by approximately 60 amino acids at the N-termini, but are otherwise nearly identical. Note that both full-length and ZMIZ1short contain all currently annotated functional protein domains. (c) RT-PCR analysis confirmed that ZMIZ1short is expressed in MCF7, but not in the other human cell lines tested. (d) Quantitative RT-PCR performed on human SCCs shows increased tumor-specific expression of ZMIZ1short. Dotted lines indicate the average Ct values for normal skin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672356&req=5

Figure 1: Tumor-specific expression of ZMIZ1short(a) Diagram of the ZMIZ1 locus in mouse and human. The human alternative promoter is located in intron 6 and drives expression of the ZMIZ1short transcript. This transcript is similar to the transcript produced by SB transposon insertion into mouse intron 8. (b) The amino acid sequence of human and mouse short-forms differs by approximately 60 amino acids at the N-termini, but are otherwise nearly identical. Note that both full-length and ZMIZ1short contain all currently annotated functional protein domains. (c) RT-PCR analysis confirmed that ZMIZ1short is expressed in MCF7, but not in the other human cell lines tested. (d) Quantitative RT-PCR performed on human SCCs shows increased tumor-specific expression of ZMIZ1short. Dotted lines indicate the average Ct values for normal skin.
Mentions: We recently identified Zmiz1 as a cancer gene important for the induction of cutaneous SCC using SB transposon mutagenesis (Dupuy et al., 2009). Significantly, all insertions were located within intron 8, and oriented in such a way as to promote expression of a truncated transcript including exons 9-24 (Figure 1a). Importantly, the SB-induced transcript strongly resembles an endogenous human ZMIZ1 isoform (uc001kag-2), which includes an alternative promoter and exon that is spliced into exon 7 of the full-length transcript (Figure 1a).

Bottom Line: Here we show that transposon-induced mutations in Zmiz1 drive expression of a truncated transcript that is similar to an alternative endogenous ZMIZ1 transcript found to be overexpressed in human SCCs relative to normal skin.In addition, we found that the alternative Zmiz1 isoform has greater protein stability than its full-length counterpart.Finally, we provide evidence that ZMIZ1 is overexpressed in a significant percentage of human breast, ovarian, and colon cancers in addition to human SCCs, suggesting that ZMIZ1 may play a broader role in epithelial cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

ABSTRACT
Cutaneous squamous cell carcinoma (SCC) is the second most common form of cancer in the human population, yet the underlying genetic mechanisms contributing to the disease are not well understood. We recently identified Zmiz1 as a candidate oncogene in nonmelanoma skin cancer through a transposon mutagenesis screen. Here we show that transposon-induced mutations in Zmiz1 drive expression of a truncated transcript that is similar to an alternative endogenous ZMIZ1 transcript found to be overexpressed in human SCCs relative to normal skin. We also describe an original mouse model of invasive keratoacanthoma driven by skin-specific expression of the truncated Zmiz1 transcript. Unlike most mouse models, Zmiz1-induced skin tumors develop rapidly and in the absence of promoting agents such as phorbol esters. In addition, we found that the alternative Zmiz1 isoform has greater protein stability than its full-length counterpart. Finally, we provide evidence that ZMIZ1 is overexpressed in a significant percentage of human breast, ovarian, and colon cancers in addition to human SCCs, suggesting that ZMIZ1 may play a broader role in epithelial cancers.

Show MeSH
Related in: MedlinePlus